Challenging the notion of endothelial infection by SARS-CoV-2: insights from the current scientific evidence
Frontiers in Immunology,
Год журнала:
2025,
Номер
16
Опубликована: Фев. 4, 2025
IntroductionCoronavirus
disease
2019
(COVID-19),
caused
by
SARS-CoV-2,
is
a
public
health
emergency
with
phenotypes
ranging
from
asymptomatic
to
severe
sequelae
that
can
lead
multiple
organ
failure
and
death
(1,
2).
SARS-CoV-2
efficiently
infects
airway
epithelial
cells
alveolar
pneumocytes,
causing
in
high
viral
loads
inflammatory
responses,
including
the
interferon
response
(3).
In
hospitalized
patients,
COVID-19
increases
risk
of
venous
arterial
thromboembolic
events
due
vascular
barrier
failure,
edema,
endotheliitis,
thrombosis,
cell
infiltration
(4,
5).
Hypercoagulation
micro-
macro-circulatory
thrombosis
are
major
causes
(6).
Although
many
people
have
survived
without
long-term
symptoms,
considerable
portion
survivors
reportedly
continuing
cardiovascular
issues
such
as
coagulopathy
or
bleeding
disorders
(7).
This
suggests
that,
addition
respiratory
epithelium,
endothelium
lining
blood
vessels
may
also
be
impacted
infection.
The
pathophysiology
has
been
explored
recent
reviews
(reviewed
(8,
9)).
Due
conflicting
data,
there
ongoing
controversy
about
endothelial
tropism
(refers
ability
interact
cells)
productive
infection
(viral
replication
within
ECs)
SARS-CoV-2.
Here,
we
share
our
perspective
on
challenging
notion
infection,
drawing
insights
current
scientific
evidence.Endothelial
dysfunction
hypercoagulation
COVID-19The
endothelium,
which
lines
inside
arteries,
crucial
for
controlling
tone
preserving
homeostasis
(10).
Disseminated
intravascular
coagulation
(DIC),
vasculitis,
all
attributable
damage
(11,
12).
Numerous
prevalent
viruses
bacteria
found
directly
infect
ECs,
necrosis,
apoptosis
and/or
vessel
wall
(13-15).
Upon
Dengue,
Hantaan,
Marburg,
Lassa,
Ebola,
both
immune
non-immune
(including
cells,
monocytes,
macrophages)
express
tissue
factor
(TF),
leading
often
culminating
disseminated
(DIC)
(16-20).
Studies
demonstrated
Marburg
(ECs)
replicate
them,
reviewed
detail
elsewhere
(13,
21,
22).
However,
it
remains
unclear
whether
exhibits
similar
phenomenon
observations.
less
studied
than
epithelium
pneumocytes
(10,
23-25).
Despite
thromboprophylaxis,
31-49%
care
patients
had
thromboembolism
(26-30).
shows
impairment
must
addressed
aggressively
prevent
thrombosis.
driven
lung-induced
systemic
inflammation
upon
injury
direct
Several
pro-inflammatory
cytokines
TNF-α,
IL-1α,
IL-1β,
IL-6,
IL-8,
MCP-1,
IFN-
responsible
cytokine
storm
(31,
32)
induce
COVID-19-associated
(CAC)
via
expression
TF
macrophages
T
(33-40).
IL-6
signaling
complex
damages
liver
sinusoidal
ECs
produces
injury,
suggesting
cause
(41).
Syrian
hamster
model
showed
type
I
dysregulation
non-respiratory
tissues
like
heart
kidney,
shedding
light
multiorgan
possible
post-acute
(42).
Spike
Nucleocapsid
protein
activate
inducing
mitochondrial
dysfunction,
vasculopathy,
(43,
44)
(Figure
1).
Furthermore,
study
early
host
declines
aging,
potentially
contributing
increased
severity
(45).Proposed
novel
(co)-receptors
entry
SARS-CoV
utilize
human
ACE2
an
receptor
TMPRSS2,
primarily
expressed
digestive
tracts,
co-factor
degrade
extracellular
matrix
proteins
(46).
variably
smooth
muscle
pericytes
across
organs,
facilitating
dissemination
into
circulatory
system.
studies,
in-house
immunohistochemistry,
humanized
mice
hACE2
brain
but
not
lung,
gastrointestinal,
renal
vessels,
employ
hACE2-dependent
independent
mechanisms
(47)
1B).
Low
TMPRSS2
limits
(48).
Thus,
variations
different
microvascular
beds,
alternative
receptors
facilitate
infectious
particles.
Supporting
this
concept,
numerous
additional
identified
over
past
three
years
relevant
particle
ECs.
Endosomal
cysteine
peptidases
cathepsins
B
L
spike
(S)
protein,
enhancing
(49-51).
binds
heparan
sulfate,
sialic
acid-containing
glycoproteins,
gangliosides
(52,
53).
Proteolytic
cleavage
at
furin-type
sites
S
exposes
conserved
motif
interacts
Neuropilin-1/2
receptors,
significantly
increasing
infectivity
(54,
55).
Vimentin,
CD147,
TMEM106B
co-receptors
though
role
pathology
lacks
experimental
validation
(56-59).
Further
research
needed
confirm
these
vivo
relevance.Controversies
Endotheliitis
regarded
immune-inflammatory
forming
inner
surface
association
consequence
pathogen
invasion.
Systemic
endotheliitis
(60).
Human
autopsies,
non-human
primates
(NHPs)
models
sporadic
consistently
observed
hamsters
(61,
62).
Compared
healthy
individuals,
circulating
markers
platelet
activation
elevated
(63).
Evidence
myeloid
polarization,
levels
shed
CD16
CD163,
linked
proinflammatory
related
poor
clinical
outcomes
(64).
Elevated
D-dimer
thrombocytopenia
could
explained
dysregulated
microthrombus
formation
complicated
(65).
Consecutively,
COVID-19,
hypoxia
pulmonary
might
classic
acute
distress
syndrome
(ARDS)
(66).
compared
controls,
isolated
lungs
challenged
lipopolysaccharide
tumor
necrosis
alpha
pro-coagulant
activity
PAI-1,
decreased
fibrinolytic
potential,
emphasizing
features
ARDS
(67).Earlier
studies
support
particles
were
detected
highly
vascularized
organs
plays
fundamental
(24,
68-76).
Initial
transmission
electron
microscopy
(TEM)
revealed
presence
kidney
autopsy
samples
(76-78).
owing
challenges
interpreting
TEM
variability
experience
those
images,
debatable
(76,
79,
80).
Irrespective
controversies,
evidence
indicate
coated
vesicles
multivesicular
bodies
closely
mimic
even
lung
uncommonly
misinterpreted
(81).
thrombo-inflammatory
phenotype,
no
definitive
animal
biopsies
yet
shown
(82-85).
macrovascular
resistant
overexpression
necessary
(86-89).
Montezano
et
al.
recombinant
protein-1
induced
enzymatic
vitro
(90).
On
ex
cultures
patient
who
signs
virus
following
immunohistochemical
labeling
(91).
primed
(IL-1)
produced
more
cytokines,
(92).
two
separate
investigations
(MOI=0.5-3
after
2
hours
adsorption)
(93,
94).Based
findings,
hypothesize
prior
reports
universal
hallmark
illness
restricted
certain
groups
episodes.
this,
carefully
evaluated
immunoreactivity
(N)
Protein
slices
translational
preclinical
(transgenic
K18-hACE2
(expression
cells),
hACE2-KI
(global
knock-in
replacing
mouse
ACE2),
hamsters,
African
green
monkeys
(AGM)
postmortem
samples.
A
board-certified
veterinary
pathologist
(N.A.C.)
immunohistochemically
analyzed
hundreds
previous
each
species
(45,
61,
62,
69,
95-99).
PCR-positive
clear
hyaline
membrane
AGMs
7
days
post-infection
(dpi)
N
Protein,
antigen
only
present
during
phase
2A
2B).
K18-hACE2,
NHPs,
ACE2-KI
varying
decreasing
hamsters.
No
antigens
2C-E).
To
further
absence
performed
duplex
fluorescent
IHC
targeting
(CD34
CD31)
protein.
AGM
mouse,
luminal
exclusively
displayed
evidenced
colocalization
4DPI
2F-G).
EC
mediators
COVID-19Collectively,
findings
group
others
question
universality
SARS-
CoV-2's
infectivity.
Because
active
associated
pro-inflammation,
activating
immunothrombosis
complement
activation,
antiphospholipid
antibodies,
so
on.
treated
sera
(n=118)
anti-cardiolipin
IgG/IgM
anti-phosphatidlyserine/prothrombin
(anti-PS/PT)
IgG/IgM-driven
elevation
adhesion
E-selectin,
VCAM-1,
ICAM-1
(100-102).
Infection-induced
IL1β,
TNFα,
stimulate
coagulation,
influence
thrombin
generation,
fibrin
formation,
TF-dependent
responses
protease-activated
(PARs)
(6,
103-107)
2H).
induces
production
superoxide
anion
release
DNA
(mtDNA),
Toll-like
9
(TLR9)
NFκ-B.
Consequently,
orchestrates
genes,
pathological
processes
(108).
highlighted
changes
lipid
profiles
COVID-19.
Among
most
commonly
reductions
serum
cholesterol
ApoA1
levels,
coupled
triglycerides
(109).
Lipidomic
analysis
eicosanoids
potential
contributor
dysfunction.
aberrant
(ECM)
controls
balance
repair
(110).
confirmed
Hyaluronan
important
compound
ECM
vital
systems
(111).
characterized
MMP-1
growth
(VEGF)-A,
correlated
(112).
More
50%
experienced
moderate
cases
reduced
diffusion
fibrotic
changes,
(113).
detailed
(114).The
glycocalyx
(EG)
maintaining
homeostasis,
(115).
EG
surface,
plasma
components
syndecan-1,
hyaluronan.
These
biomarkers,
along
hsCRP,
procalcitonin,
mortality
(116-118).
despite
underlying
still
fully
understood
(118-122).
several
drugs,
heparin
tocilizumab,
already
being
used
treatment
protect
(123-126).
Marine
algae
extracts,
fucoidan
rhamnan
sulfate
(RS)
restore
(127,
128).
Specifically,
fucoidan,
(HS)
mimetic,
reduce
restoration
serum(125).
Vascular
targeted
therapy
(84,
129,
130).
drugs
exhibit
multifunctional
properties;
however,
agents
specifically
aimed
improving
structure
integrity
reported
date.
Nevertheless,
regimens
protection
applied
practice
patients.
approaches
comprehensively
(129,
131).
Most
extracellularvesicles
(EVs)
originate
platelets
erythrocytes
(132).
Under
physiological
conditions,
proportion
EVs
secreted
relatively
low,
notably
conditions
marked
released
contain
markers,
endoglin/CD105,
E-selectinCD62E,
S-endo/CD146,
cadherin/CD144,
molecule
1/
CD31,
intercellular
1
/CD54
(133).
carrying
bloodstream
thereby
COVID-19-related
(134,
135).
Given
critical
prospective
appears
preexisting
various
states
(e.g.,
diabetes,
atherosclerosis,
hypertension)
vulnerable
course
(136).
For
instance,
among
comorbidities,
diabetes
mellitus
(DM)
was
frequently
(10.9%
cases)
condition
(137).
China,
Europe,
UK
US
when
DM
acquire
they
likely
develop
complications,
require
ICU
hospitalization,
die
(138-140).
root
chronic
together
SARS-CoV-2-mediated
result
microcirculation
multi-organ
failure.ConclusionExperimental
unlikely
productively
cells.
Instead,
mediators,
components,
vesicles,
lipids/lipoproteins,
thrombin,
primary
drivers
Additionally,
accumulating
indicates
disrupts
altering
permeability,
adhesion,
mechanosensing,
antithrombotic
anti-inflammatory
functions.Given
mixed
involvement
(co)-receptors,
needed.
First,
developing
better
demonstrate
help
identify
validate
Second,
possibility
enters
effective
replication.
trigger
significant
signaling,
rapid
RNA
degradation
render
undetectable.
hypotheses
warrant
investigation.Besides,
variation
detection
methodological
differences,
sampling
techniques,
sensitivity
methods,
models.
addition,
biological
variability,
differences
population
severity,
lay
studies.
systematic
review
required
contributes
discrepancies.
tested
researchers
dissect
out
pathogen-host
interactions
effects
interventions,
progression,
between
animals
humans
relevance
findings.Alternatively,
infected
cleared
system
mechanisms,
phagocytosis
macrophages,
through
responses.
make
detect
infections
layer,
removed
before
adequately
identified.
considering
typically
sample
time
points,
likelihood
occurring
low.
investigate
draw
well-informed
conclusion,
ensuring
clearance
accounted
analysis.Nonetheless,
confirms
making
therapeutic
target.
Addressing
individuals
hyperinflammation
hypercoagulation.
mitigate
pro-thrombotic
International
Society
Thrombosis
Haemostasis
(ISTH)
recommends
standard
thromboprophylaxis
low
molecular
weight
unfractionated
(LMWH/UFH)
unless
contraindicated
(141).
Язык: Английский
Impaired immune reconstitution in HIV infection: the role of CD4+ T-cell-associated NKG2D ligands, CD4+ T-cell subsets imbalance, and immune function deficiency
Frontiers in Immunology,
Год журнала:
2025,
Номер
16
Опубликована: Фев. 21, 2025
The
role
of
natural
killer
(NK)
cells,
which
mediate
innate
immunity,
in
the
immune
reconstitution
people
living
with
HIV
(PLWH)
remains
unclear.
Our
previous
research
indicated
that
early
activation
CD56dimCD16dim/-
NK
cells
plays
an
important
recovery
CD4+
T
immunological
non-responders
(INRs)
after
ART.
This
study
mainly
focuses
on
profiles
cell
receptors
and
their
relative
ligands
for
exhibited
INRs
responders
(IRs)
order
to
analyze
impact
differential
status
PLWH
receiving
included
66
who
had
been
ART
4
years,
comprising
32
34
IRs.
Using
flow
cytometry,
we
examined
expression
PBMCs,
as
well
differentiation
cells.
NKG2D
ligands,
including
MICA/B
ULBP2-5,
is
elevated
prior
Further
found
CD95
MICA/B+CD4+
ULBP2-5+CD4+
was
higher
before
compared
Simultaneously,
percentages
death
receptor
were
negatively
correlated
T-cell
counts
ΔCD4.
Among
subsets,
imbalance
persists
Tcm
Temra
subsets
both
IRs,
or
exhibit
levels
activation,
proliferation,
exhaustion,
apoptosis
initiation.
However,
proliferation
normalize
post-ART,
while
exhaustion
remain
significantly
elevated.
Regardless
ART,
anti-apoptotic
capacity
still
lower
than
IRs
healthy
controls
(HCs).
Before
frequency
CD31
naive
HCs.
Following
amounts
CD31+
Tn
from
impaired
upregulation
related
associated
increased
susceptibility
cell-mediated
killing.
may
poor
co-expressing
NKG2D-related
ligands.
subset
homeostasis
are
outcomes.
Язык: Английский
CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction
eLife,
Год журнала:
2024,
Номер
13
Опубликована: Апрель 30, 2024
Microgliosis
plays
a
critical
role
in
diet-induced
hypothalamic
inflammation.
A
few
hours
after
high-fat
diet
(HFD),
microglia
shift
to
an
inflammatory
phenotype,
and
prolonged
fat
consumption
leads
the
recruitment
of
bone
marrow-derived
cells
hypothalamus.
However,
transcriptional
signatures
functions
these
remain
unclear.
Using
dual-reporter
mice,
this
study
reveals
that
CX3CR1-positive
exhibit
minimal
changes
response
HFD,
while
significant
differences
emerge
between
CCR2-positive
recruited
myeloid
cells,
particularly
affecting
chemotaxis.
These
also
show
sex-specific
impacting
neurodegeneration
thermogenesis.
The
chemokine
receptor
CXCR3
is
emphasized
for
its
chemotaxis,
displaying
notable
resident
microglia,
requiring
further
investigation.
Central
immunoneutralization
CXCL10,
ligand
CXCR3,
resulted
increased
body
mass
decreased
energy
expenditure,
especially
females.
Systemic
chemical
inhibition
led
metabolic
changes,
including
mass,
reduced
elevated
blood
leptin,
glucose
intolerance,
insulin
levels.
This
elucidates
inflammation
identifies
CXCR3-expressing
immune
as
protective
outcomes
linked
HFD
consumption,
establishing
new
concept
obesity-related
Язык: Английский
S309-CAR-NK cells bind the Omicron variants in vitro and reduce SARS-CoV-2 viral loads in humanized ACE2-NSG mice
Journal of Virology,
Год журнала:
2024,
Номер
98(6)
Опубликована: Май 20, 2024
ABSTRACT
Recent
progress
on
chimeric
antigen
receptor
(CAR)-NK
cells
has
shown
promising
results
in
treating
CD19-positive
lymphoid
tumors
with
minimal
toxicities
[including
graft
versus
host
disease
(GvHD)
and
cytokine
release
syndrome
(CRS)
clinical
trials.
Nevertheless,
the
use
of
CAR-NK
combating
viral
infections
not
yet
been
fully
explored.
Previous
studies
have
that
expressing
S309
single-chain
fragment
variable
(scFv),
hereinafter
S309-CAR-NK
cells,
can
bind
to
SARS-CoV-2
wildtype
pseudotyped
virus
(PV)
effectively
kill
wild-type
spike
protein
vitro
.
In
this
study,
we
further
demonstrate
different
variants,
including
B.1.617.2
(Delta),
B.1.621
(Mu),
B.1.1.529
(Omicron)
variants
We
also
show
reduce
loads
NOD/SCID
gamma
(NSG)
mice
human
angiotensin-converting
enzyme
2
(hACE2)
challenged
(strain
USA/WA1/2020).
Our
study
demonstrates
potential
for
inhibiting
infection
by
treatment
COVID-19
patients
unresponsive
otherwise
currently
available
therapeutics.
IMPORTANCE
Chimeric
be
“off-the-shelf”
products
treat
various
diseases,
cancer,
infections,
autoimmune
diseases.
engineered
natural
killer
(NK)
express
target
Spike
SARS-CoV-2,
cells.
shows
are
effective
against
variants.
The
(i)
directly
(PV),
(ii)
competitively
PV
293T
(293T-hACE2
cells),
(iii)
specifically
lyse
A549
protein,
(iv)
significantly
USA/WA1/2020)
lungs
hACE2
(hACE2-NSG
mice).
Altogether,
current
immunotherapy
as
an
alternative
patients.
Язык: Английский
CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Янв. 20, 2024
Abstract
Microgliosis
is
an
important
component
of
diet-induced
hypothalamic
inflammation
in
obesity.
A
few
hours
after
the
introduction
a
high-fat
diet,
mediobasal
hypothalamus
resident
microglia
undergo
morphological
and
functional
changes
toward
inflammatory
phenotype.
If
consumption
large
amounts
dietary
fats
persists
for
long
periods,
bone
marrow-
derived
myeloid
cells
are
recruited
integrated
into
new
landscape
microglia.
However,
it
currently
unknown
what
transcriptional
signatures
specific
functions
exerted
by
either
or
subsets
Here,
elucidation
revealed
that
only
minor
response
to
fats;
however,
under
there
major
differences
between
immune
with
impact
on
chemotaxis.
In
addition,
CCR2+
peripheral
cells,
females
males
transcripts
involved
neurodegeneration
thermogenesis.
The
chemokine
receptor
CXCR3
emerged
as
one
components
chemotaxis
greatest
difference
microglia,
thus,
was
elected
further
intervention.
immunoneutralization
CXCL10,
ligands
CXCR3,
resulted
increased
body
mass
gain
reduced
energy
expenditure,
particularly
females.
Furthermore,
chemical
inhibition
much
greater
change
phenotype
gain,
blood
leptin,
glucose
intolerance,
insulin.
Thus,
this
study
has
elucidated
obesity,
identifying
chemokines
relevant
subset
genes
undergoing
regulation.
we
showed
expressing
protective,
rather
than
detrimental
role
metabolic
outcomes
promoted
establishing
concept
obesity-associated
inflammation.
Язык: Английский
Understanding emerging and re-emerging viruses to facilitate pandemic preparedness
Nature Microbiology,
Год журнала:
2024,
Номер
9(9), С. 2208 - 2211
Опубликована: Авг. 28, 2024
Язык: Английский
CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction
Опубликована: Окт. 11, 2024
Microgliosis
is
an
important
component
of
diet-induced
hypothalamic
inflammation
in
obesity.
A
few
hours
after
the
introduction
a
high-fat
diet,
mediobasal
hypothalamus
resident
microglia
undergo
morphological
and
functional
changes
toward
inflammatory
phenotype.
If
consumption
large
amounts
dietary
fats
persists
for
long
periods,
bone
marrow-
derived
myeloid
cells
are
recruited
integrated
into
new
landscape
microglia.
However,
it
currently
unknown
what
transcriptional
signatures
specific
functions
exerted
by
either
or
subsets
Here,
elucidation
revealed
that
only
minor
response
to
fats;
however,
under
there
major
differences
between
immune
with
impact
on
chemotaxis.
In
addition,
CCR2+
peripheral
cells,
females
males
transcripts
involved
neurodegeneration
thermogenesis.
The
chemokine
receptor
CXCR3
emerged
as
one
components
chemotaxis
greatest
difference
microglia,
thus,
was
elected
further
intervention.
immunoneutralization
CXCL10,
ligands
CXCR3,
resulted
increased
body
mass
gain
reduced
energy
expenditure,
particularly
females.
Furthermore,
chemical
inhibition
much
greater
change
phenotype
gain,
blood
leptin,
glucose
intolerance,
insulin.
Thus,
this
study
has
elucidated
obesity,
identifying
chemokines
relevant
subset
genes
undergoing
regulation.
we
showed
expressing
protective,
rather
than
detrimental
role
metabolic
outcomes
promoted
establishing
concept
obesity-associated
inflammation.
Язык: Английский
Continuing Discoveries in Immunogenetics and Computational Immunology: An Update
Elsevier eBooks,
Год журнала:
2024,
Номер
unknown
Опубликована: Янв. 1, 2024
Язык: Английский
CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction
eLife,
Год журнала:
2024,
Номер
13
Опубликована: Ноя. 13, 2024
Microgliosis
plays
a
critical
role
in
diet-induced
hypothalamic
inflammation.
A
few
hours
after
high-fat
diet
(HFD),
microglia
shift
to
an
inflammatory
phenotype,
and
prolonged
fat
consumption
leads
the
recruitment
of
bone
marrow-derived
cells
hypothalamus.
However,
transcriptional
signatures
functions
these
remain
unclear.
Using
dual-reporter
mice,
this
study
reveals
that
CX3CR1-positive
exhibit
minimal
changes
response
HFD,
while
significant
differences
emerge
between
CCR2-positive
recruited
myeloid
cells,
particularly
affecting
chemotaxis.
These
also
show
sex-specific
impacting
neurodegeneration
thermogenesis.
The
chemokine
receptor
CXCR3
is
emphasized
for
its
chemotaxis,
displaying
notable
resident
microglia,
requiring
further
investigation.
Central
immunoneutralization
CXCL10,
ligand
CXCR3,
resulted
increased
body
mass
decreased
energy
expenditure,
especially
females.
Systemic
chemical
inhibition
led
metabolic
changes,
including
mass,
reduced
elevated
blood
leptin,
glucose
intolerance,
insulin
levels.
This
elucidates
inflammation
identifies
CXCR3-expressing
immune
as
protective
outcomes
linked
HFD
consumption,
establishing
new
concept
obesity-related
Язык: Английский